1362557110 diabetic foot an overview

THE DIABETIC FOOT: AN OVERVIEW September 2004

Andrew J M Boulton MD, DSc (Hon), FRCPProfessor of Medicine, University of ManchesterConsultant Physician, Manchester Royal

Infirmary, Manchester, UK.Professor of Medicine, University of Miami,

Miami, Fl, USA

AN EXPERT

‘An expert is someone who comes a long way

- and brings slides’

Henry Miller

Henry Miller

A SPECIALIST

‘A Specialist is a man who knows more and more about less and less’

William Mayo

‘Mind like parachute –Does not work if not open.’

Charlie Chan

Diabetic foot care is the PITS:-

PreventionIdentificationTreatmentService

THE DIABETIC FOOT: Two decades of progress

1986: First Malvern Diabetic Foot Meeting1987: Foot Council of ADA formed1991: First International Diabetic Foot Meeting1998: Diabetic Foot Study Group of EASD founded1998: Japanese and Alfadiem symposia on the foot1999: International Consensus group publishes

Guidelines on management

THE DIABETIC FOOT: no longer the Cinderella of diabetic complications

Publications listed on Medline on the diabetic foot / total diabetes publications

1979-1988: 0.7%1989-1996: 1.4%1997-2003: 2.7%

INTERNATIONAL MEETINGS ON THE DIABETIC FOOT

1991 First meeting – 250 delegates1995 Second meeting – 450 delegates1999 Third meeting – 600 delegates2003 Fourth meeting – 700 delegates

‘Diabetes itself may play an active part in the causation of perforating ulcers…….

..And it is abundantly evident that the actual cause of the perforating ulcers was a peripheral nerve degeneration

TD Pryce, 1887

Paul Brand CBE, MD, FRCS 1914-2003

• The Gift of Pain• Pain: the Gift nobody wants

• Surgeon and missionary: worked in leprosy and diabetes• He took the foot from art to science

Paul Brand Paul Brand

Paul Brand CBE, MD, FRCS 1914-2003

• THE ART: ‘Remove the patient’s shoes and socks and look at the feet’

• THE SCIENCE Classic studies of the relationship between pressure, time

and ulceration in the canine hind-limb

The Diabetic Foot

• Epidemiology• Causal pathways• Reducing foot pressures• Charcot Foot• Wound healing• International perspective

AMPUTATIONS IN DIABETES: TRENDS 1995-2000

• US data: steady increase in major amputations

• UK: 50% increase in one health care district

• Germany: no evidence of decrease

• Sweden: 78% decrease in amputations

CDC, 1997 Anonymous, 1997 Stiegler et al, 1998 Larrson et al, 1995 Trautner et al, 2001

Prevalence of Foot Ulcers and Amputationsin Diabetes

PrevalenceAuthor Yr Country Ulceration Amputation

Borssen 1990 Sweden 0.75%

Moss 1992 USA 3.6%

Kumar 1994 UK 1.4%

Carrington 1996 UK 4.8% 1.4%

Vozar 1997 Slovakia 2.5% 0.9%

Pendsey 1994 India 3.6% -

Van Rensbe 1995 S. Africa 11.2% -

U-Roven 1998 Slovenia 7.1% -

Belhadj 1998 Algeria 11.9% 6.7%

The Diabetic Foot


THE PAIN OF NEUROPATHY

‘Of a burning and unremitting character’

F W Pavy, 1887

PAINFUL NEUROPATHY

‘I don’t like peripheral neuritis - it interferes with work’

R D Lawrence, 1923

DIABETIC NEUROPATHY: PREVALENCE.

• UKPDS showed that >10% of patients had neuropathy at the diagnosis of Type 2 diabetes

• Neuropathy may be asymptomatic in over 50% of subjects.

• UK Community study of Type 2 patients (n=811), mean age 65 yrs. * 41.6% clinical evidence of neuropathy * 11% peripheral vascular disease

• Over 50% of older Type 2 patients have risk factors for foot ulceration

Kumar at al: 1994

UKPDS, 1998

Risk Factors for Neuropathy in UKPDS

Irene M Stratton, Rury R Holman, Andrew JM Boulton for the UKPDS group

Background to UKPDS• A multicentre, randomised clinical trial of therapies

in patients with newly diagnosed Type 2 diabetes• 5,102 subjects, mean age 53 years • Trial period 1977-1997• Recruitment ended in 1991 with main study results

in 1998• No sustained difference was seen in indices of

neuropathy between allocated treatment policies

Measures of neuropathy• Patients were assessed at entry to the study,

and then every three years for:-• vibration perception threshold (VPT)• absence of one or both ankle reflexes• erectile dysfunction (ED)

Aims

• To examine prevalence and incidence of new neuropathy we examined:-

• Age• Gender• HbA1c• Height• Waist circumference• Alcohol consumption• Smoking status• Weight

Vibration Perception Threshold

• Biothesiometer used to assess VPT at the lateral malleoli and at apex of great toes

• Abnormal VPT defined here as mean value for great toes >25 volts

Relative risk for VPT in great toes >25

12.8% prevalence at diagnosis______________________________________________________________________________________________________________________________________________________

__________

Age (per 5 years) 1.89 (1.73 to 2.07)Height (per 5 cm) 1.40 (1.32 to 1.50)Waist (per 5 cm) 1.05 (1.01 to 1.10)13.3% incidence at 12 years______________________________________________________________________________________________________________________________________________________

__________

Age (per 5 years) 1.58 (1.44 to 1.73)Female 0.56 (0.44 to 0.70)HbA1c (per 1%) 1.07 (1.01 to 1.14)

Years from entry

Age at entry

VPT in great toes >25by age

010203040506070

0 3 6 9 12

Pro

porti

on w

ith e

vent

(%)

<50 50-59 60+

Point prevalence at 12 years 37%

Conclusions• The risk factors for these 3 indices of neuropathy

were similar for prevalent cases at diagnosis and for subsequent incident cases

• For prevalence the most important risk factor was age, but HbA1c, height, waist circumference and alcohol were also significant

• For incidence age was the most important factor, again height, HbA1c and measures of obesity were important

• Twelve years from diagnosis 71% of men and 51% of women have at least one of these indices of neuropathy

Does Neuropathy Lead to Ulceration? A Prospective

Study

– 469 diabetic patients screened in 1988– Vibration perception assessed by

biothesiometry– All foot ulcers recorded

Young et al, Diabetes Care 1994;17:557

Biothesiometer

Prospective Foot Ulcer Study

Results — Foot Ulcers

VPT<15 VPT 16-24 VPT>25

Total ulcers 1988-92 6 2 41Risk per patient 2.9% 3.4% 19.6%Risk/patient/year 0.7% 0.9% 4.9%

Causal Pathways for Foot Ulceration

• Neuropathy most important component cause (78%)

• Critical triad: neuropathy, deformity, and trauma present in 63%

• Ischemia component cause in 35%• >80% of ulcers potentially preventable

Reiber, Vileikyte et al, 1999.

The Most Common Causal Pathway to Incident Diabetic

Foot Ulcers

FOOTWEAR

• Controlled evidence for reduction of recurrent ulceration

• evidence for footwear as part of multidisciplinary approach

Uccioli et al, D.Care 1995; 18: 1376 Dargis et al, D. Care 1999; 22: 1428 Faglia et al, D. Care 2001; 245: 78

Predicting Neuropathic Foot Ulcer Risk

• North West Diabetes Foot Care Study (NWDFCS)

• Population-based prospective study in NW UK – 6 health-care districts

• 16,000 patients included in total • First study on 9,710 diabetic patients Abbott et al, Diabetic Med 2002;19:377

http://www.man.ac.uk/

NWDFCS: THE NDS

• 3 sensory modalities Vibration (128 Hz tuning fork – hallux) Pin-prick (Neurotip): dorsal distal hallux Hot/cold rods : dorsal distal hallux ALL: normal = 0, abnormal = 1 Ankle reflex: normal = 0, absent = 2,

reinforcement = 1 MAX TOTAL 5 each leg: =10

Abbott et al, 2002

NWDFCS: Results

• 9710 diabetic patients followed for 2 years• 291 ulcers developed: male to female: 1.6:1.0• NDS best baseline predictor NDS < 6: 1.1% annual ulcer incidence NDS > 6: 6.3% annual ulcer incidence

Abbott et al, 2002

Foot Pressure Studies in Diabetic Neuropathy

• High foot pressures associated with first and recurrent plantar neuropathic ulcers

• Foot Pressure abnormalities precede the appearance of neuropathy

• High foot pressures predict ulcers • Plantar callus associated with high pressure

and predicts ulcer formation Boulton et al, 1983, 1984, 1985,1986. Veves et al, 1992. Murray et al, 1996

Semi-Quantitative Foot Pressure Assessment

• Podotrack (PressureStat): a dynamic pressure print map system

• Inexpensive, easy to use in clinic or at home• Validated by comparison with optical

pedobarograph• All high pressure sites correctly identified by

trained observers

Van Schie et al: Diabetic Med 1999;16:154

‘Coming Events cast their shadows before.’

Thomas Campbell

The Diabetic Foot


Reducing Foot Pressures• Orthoses• Padded Hosiery• Removing callus• Footwear• Surgery• Injected liquid silicone Lavery et al, 1998 Veves et al, 1989, 1990 Young et al, 1992 Murray et al, 1996 Van Schie et al, 2001, 2002

Diabetic Foot 2000

• First randomized controlled trial• Podosil/saline injected under callus

at high pressure areas• Podosil: Increased plantar tissue

thickness: reduced pressures• This treatment may reduce ulcer

rates in high risk patientsVan Schie et al, Diabetes Care

2000;23:634

New TreatmentDoes injected liquid silicone reduce ulcer risk?


Silicone Injection in the High Risk Diabetic Foot

Diabetic Foot Ulcer Prevention

• Who responds best to silicone?• Podosil: Increased plantar tissue

thickness greatest in those with highest baseline foot pressure

• Those at highest risk of foot ulceration most likely to benefit from silicone injection.

Van Schie et al, Wounds 2002;14:26

Potential New TreatmentDoes injected liquid silicone reduce ulcer risk?


Diabetic Foot 2002

• Two year follow-up study• Podosil/saline injected under callus

at high pressure areas• Two year fu: pressure reduction

effects of ILS reduced: plantar tissue thickness remained increased

• This suggests that booster injections may periodically be required.

Van Schie et al, Arch Phys Med Rehabil 2002;83:919-923

Injected Liquid Silicone (ILS)

Does silicone’s pressure reducing effect last?


Classification of Diabetic Foot Ulcers

• Wagner Grades: 0-5: classical, most frequently quoted

• San Antonio: Wagner Grades and staging for ischaemia/infection

• Nottingham S(AD), SAD system• King’s College SSS: Stages 1-6

Armstrong et al, 1998Jeffcoate et al, 1999

Foster et al, 2000


UT Diabetic Wound Classification System

0 1 2 3

A Pre or postulcerative

lesion (epithelialized)

Superficial, not involving

tendon, capsule or bone

Penetrates to tendon or capsule

Penetrates to Bone

B INFECTION INFECTION INFECTION INFECTION

C ISCHEMIA ISCHEMIA ISCHEMIA ISCHEMIA

D INFECTION and ISCHEMIA

INFECTION and ISCHEMIA



Armstrong, et al, Diabetes Care, 1998Armstrong, et al, Diabetes Care, 1998

• 2 centre prospective observational study

• 194 patients followed for 6 months• Inclusion of stage (ischaemic

and/or infection) made San Antonio (UT) system a better predictor of outcome

Oyibo et al, Diabetes Care 2001;24:84

San Antonio vs Wagner classifications in wound

healing prediction


The Diabetic Foot


Factors AffectingWound Healing

Some Factors That May Influence Wound Healing

• Albumin concentration• TCpO2 concentration• Infection• Hyperglycaemia• Cytokine imbalance• Protease and inhibitor imbalance• Psychological stress

TGF- distribution in Diabetic Foot Ulcers

• TGF- 1,2 and 3 and TGF- receptor distribution in foot ulcers compared with diabetic and non-diabetic skin

• TGF- 3 expression was increased in foot ulcer biopsies

• TGF- 1 expression not increased in foot ulcers• Lack of TGF-1 upregulation may explain the

chronicity and retarded wound healing

Jude et al, Diabet Med 2002;19:440

NS DS DFU AG

TGF 1

TGF 2

TGF 3

Transforming growth factors in diabetic foot ulcers

Lack of IGF1 in Diabetic Foot Ulcers

• IGF 1 & 2 distribution in foot ulcers compared with diabetic and non-diabetic skin

• IGF 2 found throughout epidermis in all three groups

• IGF 1: absent in basal layer at ulcer edge and in fibroblasts

• Lack of expression of IGF1 may contribute to retarded wound healing

Blakytny et al, J. Pathol 2000;190:606

Matrix metalloproteinases in Diabetic Foot Ulcers

• Punch biopsies from 20 DFUs and 12 non-diabetic traumatic wounds

• MMPs 1 (x65), 2 (x6), 8(x2) and 9(x14) all increased in chronic DFUs compared to controls

• Expression of TIMP-2 decreased twofold in DFU• These findings suggest that the increased

proteolytic environment may be contributory to the chronicity of DFUs.

Lobmann et al, Diabetologia 2002;45:1011

Psychological stress and wound healing

• Anxiety/depression more common in DN: may impact adherence to off-loading Vileikyte et al, 2003

• Psychological stress slows healing of acute wounds Kiecolt-Glaser et al 1995

• Chronic stress can lead to increased IL-6 and altered MMP levels

Yang et al 2002,, Kiecolt-Glaser et al 2003

Wound Care

Factors That Enhance Wound Healing

Correct underlying condition• Control infection• Vascular reconstruction for patients with

severely compromised peripheral circulation• Adequate glycaemic control for patients

with diabetes• Off-load pressure• Maintain moist wound healing environment

Factors That Enhance Wound Healing (continued)

Adequate debridement– Removes infected and non-viable tissue– May stimulate release of endogenous

growth factors

Effect of Debridement on Healing of Diabetic Foot

Ulcers

Steed, et al. Steed, et al. J Am Coll SurgJ Am Coll Surg 1996;183:61-64. 1996;183:61-64.

100

80

60

40

20

020 40 60 10080

Patie

nts

Hea

led

(%)

Patie

nts

Hea

led

(%)

*100 µg rhPDGF-BB per gram sodium *100 µg rhPDGF-BB per gram sodium carboxymethylcellulose gel.carboxymethylcellulose gel.

Office Visits at which debridementOffice Visits at which debridementwas performed (%)was performed (%)

rhPDGF-BB*rhPDGF-BB*

PlaceboPlacebo

Common Methods to Common Methods to “Off-Load” the Foot“Off-Load” the Foot

• Bed Rest• Wheel Chair• Crutch Assisted Gait• Total Contact Casts• Felted Foam• “Half Shoes”• Therapeutic Shoes• Custom Splints• Removable Cast

Walkers

Total Contact Cast Total Contact Cast Advantages

• Forced compliance• Shortens stride

length• Decrease cadence• Reduces activity• Reduces peak

pressures

Offloading the DM Wound

Week of therapy

121086420

Cum

ulat

ive

Sur

viva

l

1.2

1.0

.8

.6

.4

.2

0.0

Device

TCC

Half Shoe

Aircast

Armstrong, et al, Diabetes Care, 2001Armstrong, et al, Diabetes Care, 2001

Activity Patterns of Persons with Diabetic Foot Ulceration: Persons with Active Ulceration may not

Adhere to a Standard Pressure-Offloading Regimen

DG ArmstrongLA LaveryHR KimbrielBP NixonAJM Boulton

From the Department of Surgery, Southern Arizona Veterans Affairs Medical Center, Tucson, AZ, USA, the Department of Medicine, Manchester Royal Infirmary, Manchester, United Kingdom, the Department of Surgery, Texas A&M University, and the Department of Medicine, University of Miami, Miami, FL, USA

Introduction

• Pressure-offloading is a critical component in treating plantar diabetic foot wounds

• Gait lab plantar pressure analysis demonstrated total contact casts (TCC) equivalent to removable cast walkers (RCW)

• Yet TCCs have been shown to be clinically superior to RCWs

Armstrong, et al, Diabetes Care, 2001 Frykberg, et al, J Foot Ankle Surg, 2000

Lavery et al, Diabetes Care, 1996

Purpose

• To evaluate the activity of persons with diabetic foot ulcerations and their adherence to their pressure offloading device.

Methods

• 20 persons were treated for UT Grade 1A neuropathic diabetic foot wounds

• All were offloaded utilizing a removable cast walker (RCW)

• Total activity was recorded (measured in activity units or steps per day) taken on a waist-worn computerized accelerometer

• We subsequently correlated this to activity recorded on a RCW-mounted accelerometer, which was not readily accessible to the patient

Results

• There were a mean 1219.1 ± 821.2 activity units (steps) taken per patient per day

• Patients logged significantly more daily activity units with the protective removable cast walker off than with it on (873.7 ± 828.0 vs. 345.3 ± 219.1, p = 0.01)

• This amounts to only 28% of total daily activity recorded while patients were wearing their removable cast walker

* p = 0.01

Activity Data: Waist vs. RCW

Conclusion

Armstrong, et al, J Amer Podiatr Med Assn, 2002Armstrong, et al, J Amer Podiatr Med Assn, 2002

• Modify RCW to make it less easily removable– “Instant” total contact cast

‘Instant Total-Contact Cast’ vs TCC: controlled trial

• TCC ‘gold standard’ but labor-intensive, expensive and time-consuming

• 2 trials in progress• a): TCC vs Instant TCC • b): Instant TCC vs Cast walker Boulton and Armstrong , 2003

‘Instant Total-Contact Cast’ vs TCC: controlled trial

• Randomized controlled trial: 38 plantar neuropathic ulcer patients randomized to instant or regular TCC

• No differences in healing times observed• Instant TCC quicker to apply and cheaper for the

duration of treatment• Any center can apply instant TCC without casting

experience• This treatment could revolutionize the management

of plantar neuropathic ulcers Katz et al , Diabetes 2004 (In press)

Studies of new therapies for neuropathic foot ulcers: time for a paradigm shift?

• Why have so many trials of dressings and other new therapies failed?

• Few if any have attended to offloading• Conclusions: we propose that all future trials

of therapies for plantar neuropathic ulcers should have standardized offloading in all treatment groups

Boulton and Jude, 2002,

Boulton and Armstrong, 2003, 2004

The effect of pressure relief on the histopathology of

diabetic foot ulcers• Randomized trial of patients with chronic

plantar diabetic neuropathic ulcers • Group A: TCC for 20 days then ulcerectomy

Group B: Ulcerectomy • Histological changes compared between the

two groups

Piaggesi et al, 2002, 2003

Histological Results

Hyperkeratosis 1.8 2.8 p<0.002

Fibrosis 1.8 2.8 p<0.007

Capillaries 2.5 0.5 p<0.001

Inflammation 1.1 3.0 P<0.001

Granulating 2.8 0.2 p<0.001

Effective offloading: histologic evidence

Piaggesi, et al, Diabetes Care, 2003Piaggesi, et al, Diabetes Care, 2003

Removable offloadingRemovable offloading Irremovable offloadingIrremovable offloading

The effect of pressure relief on the histopathology of diabetic

foot ulcers:Conclusions

• Pressure not only has a direct effect on the ulcer but also supports the chronic inflammation

• After pressure relief, the diabetic foot ulcer in many ways resembles an acute wound

• Prolonged repetitive pressure contributes to the chronicity of diabetic neuropathic foot ulcers

Piaggesi et al, 2002, 2003

Summary

• Wound healing in diabetes is impaired• Multiple factors are impaired in diabetic

wound healing• Cellular differences noted between

acute and chronic wound healing• Failure to offload pressure from plantar

neuropathic ulcers is a major contributory factor in ulcer chronicity

The future….

• Better understanding of the wound healing process in diabetes is needed

• Possibly cocktail of GFs / TIMPs?• Gene expression in chronic wound

healing• Gene therapy of wound healing in the

not too distant future?

The future….

• Role of bone marrow-derived cells? Preliminary evidence suggests that they can lead to dermal rebuilding

Badiavas & Falanga, 2003

• Role of Oestrogen? Oestrogen can enhance wound healing, possibly through

down-regulation of macrophage MIF

Ashcroft et al 2003 • Role of Androgens? Testosterone inhibits cutaneous wound healing response

in males Ashcroft & Mills 2002

The Diabetic Foot


‘To live in one land is captivity’

J. Donne

S. America

Save the diabetic foot project

Brasília, Brazil1992-2002

(A ten year educational approach to make

professionals concerned about foot problems and motivate the implementation of foot

clinics)

Pedrosa et al, Curr Diab Rep 2004

Diabetic Foot Clinics:

Implementation in Brazil -

1992 Brasília

Diabetic Foot Clinics* 1992/2001

Implemented - 34In implementation – 10

Total = 44

* outpatient basis

0

1

2

3

4

5

6

7

8

1992 1993 1994 1995 1996 1997 1998 1999 2000

DM - FemaleDM - Male

Major amputation (1992/2000)

Female: 2.67 1.72

Male: 1.11 0.71ns

Rate reduction (92-94 / 98-00)

Female = 71,42%

Male = 50%

For one mistake made for not knowing, ten mistakes are made for not looking.

J A Lindsay

“Before I came to this lecture, I was confused.

After hearing it I am still confused, but on a higher level”

Enrico Fermi

“...It ought, however, to be remembered, that more credit is due to the surgeon who saves one limb, than to he who amputates twenty.”

Edinburgh Med Surg J. 1805;1:187-193.

Who Rules the World?

‘ Do not follow where the path may lead,

go instead where there is no path, and leave a trail ’

Anon

Inferior physicians treat the full-blown diseaseGood physicians treat the

disease before it appearsSuperior physicians prevent the disease

Chinese proverb

I hear and I forgetI see and I rememberI do and I understand

Chinese proverb

‘The surest way not to fail is to be determined to succeed’

R. Sheridan

‘If you always do what you always did..

You will always get what you always got

Liam Donaldson

Success consists of going from failure to failure – without loss of enthusiasm

Winston Churchill

‘Prediction is always difficult – especially when it concerns the future.’

Wilde

The old believe everything

The middle-aged suspect everything

The young know everything

Oscar Wilde

The truth is rarely pure and never simple

Oscar Wilde

An ulcer is only a symptom of an underlying diathesis

Swartz, 1910

www.DiabeticFootOnline.com


International Guidelines on the Outpatient Management of

Patients with Peripheral Neuropathy

Annual Review of the Diabetic Patient

• Should include:– Patient history

• Age diabetes, lifestyle,social circumstancessymptoms

– Foot examination• Skin status, sweating,

infection, blistering,joint mobility, gait,shoes

• Tests– Pin prick test– Light touch– Vibration test– Pressure perception– Ankle reflex

I marvel that society would pay a surgeon a large sum of money to remove a person’s leg — but nothing to save it.

George Bernard Shaw

ConclusionConclusion“If you don’t know where you’re

going, you’ll end up someplace else.” -Yogi Berra


“The art of life is the art of avoiding pain; and he is the

best pilot, who steers clearest of the rocks and shoals with

which it is beset.”

Thomas Jefferson

Use of Apligraf (Graftskin) in diabetic foot ulcers

• Randomized trial in 208 patients• Graftskin vs saline gauze + standard

treatment• 56% (Graftskin) vs 38% (control)

healing (p=0.004)• Time to closure 65 vs 90 days• Graftskin is a useful adjunct to best

standard care

Veves, Falanga, Armstrong, Sabolinski, Diabetes Care, 2001

A Study of Promogran in Diabetic foot ulceration

• Randomized, 11 centre trial: 276 subjects, neuropathic plantar ulcers, 12 week study

• Promogran vs. moistened gauze• Offloading constant in each centre, but

technique ‘left to individual’ • Results: 37% Promogran healed vs 28%: ns• Conclusions: Promogran safe and may be

useful for neuropathic ulcers! Veves et al, Arch Surg 2002;137:822

Results

• 30% of the patients in the study recorded more daily activity units while wearing the device (best behaved)– still only wore the device for a total of 60%

of their total daily activity

Camillo Golgi, 1898

• On the structure of nerve cells• On the structure of the nerve cells of the

spinal ganglia

Golgi, Arch Ital Biol, 1898

PAIN

‘I shall never be free until I can feel pain’

Leprosy patient in Madras: cited by Dr Paul Brand

‘If I were to choose between pain and nothing ….. I would choose pain’

William Faulkner

InflammationInflammation Proliferation/Proliferation/RegenerationRegeneration RemodellingRemodelling

WoundWoundHealingHealing

Phases of Wound Healing

Inflammation Phase

InjuryInjury

Clot FormationClot Formation(platelet aggregation)(platelet aggregation)

Release of chemotactic agentsRelease of chemotactic agents(platelet degranulation)(platelet degranulation)

Orderly recruitment of cellsOrderly recruitment of cellsinto wound siteinto wound site

Cell Influx Into Wound Site1

1. Pierce, et al 1. Pierce, et al J Cell BiochemJ Cell Biochem 1991;45:319- 1991;45:319-326326

NeutrophilsNeutrophils

MacrophagesMacrophages

FibroblastsFibroblasts

00 22 44 66 1414 2828 4242

Days Post-InjuryDays Post-Injury

88 1010

Wound Healing CascadeEarly CascadeEarly Cascade Late CascadeLate Cascade

PMNsPMNs

MacrophagesMacrophages

FibroblastsFibroblasts

Granulation TissueGranulation Tissue

Wound StrengthWound Strength

AutocrineAutocrine

AutocrineAutocrine

GFs PDGF TGF-ß1GFs PDGF TGF-ß1

PDGF-AA TGF-ß1PDGF-AA TGF-ß1

Procollagen 1Procollagen 1Extracellular MatrixExtracellular Matrix

55 1010 151500

WoundingWounding ((DaysDays))

CONCLUSIONS

• Possible future studies with higher doses

• Use of oral bisphosphonates?• Earlier diagnosis essential• Better diagnostic markers• Do not forget the words of Dr Jean-

Martin Charcot ……………………….

CHARCOT NEUROARTHROPATHY

How often have I seen persons, not yet familiar with this arthropathy,

misunderstand its real nature, and wholly preoccupied with the local affection, even absolutely forget that behind the disease of the joint there was a disease far more important in character and which really

dominated the situation J M Charcot 1881

Chronic Non-healing Wounds

• Chronic non-healing wounds occur when the normal healing process is compromised

• Ultimately, chronic wounds may fail to heal because of decreased growth factor activity or increased protease activity, or both

Roles of Growth Factors in Wound Healing

• All three phases of wound healing• Chemotaxis• Mitogenesis• Stimulate angiogenesis• Influence synthesis and degradation

of extracellular matrix• Influence synthesis of other

cytokines and growth factors

Nitric oxide in wound healing

• NO is important in the wound healing Moncada 1991, Schaffer 1997

• Reduced NO production may impair wound healingSchaffer 1997, Boykin 1999

• NO and other nitrogenous free radicals (superoxide, peroxynitrite) cause tissue destructionRadi 1991, Beckman 1990

Nitric Oxide Synthase and Arginase in Diabetic Foot Ulcers

• L Arginine metabolized by NO synthase or Arginase

• Enzyme activity measured in foot ulcers, diabetic and normal skin

• NO synthase and Arginase activities increased in foot ulcers. TGF beta 1 decreased in foot ulcers

• These findings could explain impaired healing: ? Arginase effect on callus

Jude et al, Diabetologia 1999;42:748

Adjunctive Wound Healing Modalities

• Bioengineered Tissue• Growth Factors• Hyperbaric Oxygen• Vacuum-assisted therapy• Larvatherapy• Antibiotic-impregnated beads

“In God we trust.

…all others must show data”

anon

Cultured Human Dermis (Dermagraft)

31.738.5

50.8

0

10

20

30

40

50

60

Control (n =126)

CulturedHuman Dermis(n = 109)CulturedHuman DermisTR (n = 61)

% H

ealed in 12 %

Healed in 12

Weeks

Weeks

Pollack,et. al. Wounds, 1997Pollack,et. al. Wounds, 1997

MANCHESTERLoretta VileikyteCaroline AbbottFrag AbouaeshaGillian AshcroftAnne CarringtonPeter CavanaghCuong DangMark FergusonDevaka FernandoNicky JacksonEd JudeEvangelos KatoulisAnn Knowles

Sudhesh KumarRayaz MalikEwan MassonSam OyiboY PrasadAnne RoscoePeter SelbyNick TentolourisDavid TomlinsonSteve TomlinsonCarine Van SchieAris VevesMatthew Young

United Kingdom SHEFFIELDJohn WardBill ArmstrongRick BettsChris FranksColin HardistyGraham KnightPaul NewrickJohn ScarpelloSolomon Tesfaye

ELSEWHEREPaul BakerNish ChaturvediHenry ConnorMollie DonohoeMike EdmondsAli FosterSimon PagePK ThomasBob Young

USA

MIAMIJay SkylerJohn BowkerRick CutfieldF Collado-MesaB Miranda-PalmaMark MizelJay Sosenko

ELSEWHEREDavid ArmstrongPeter CavanaghLarry HarklessLarry LaveryBen LipskyMark PeyrotGary PittengerGayle ReiberRichard RubinJan UlbrechtArthur Vinik

THE WORLDBELGIUMKristien Van AckerBRAZILHermelinda PedrosaGERMANYDan ZieglerGREECENicolas KatsilambrosEvangelos KatoulisChristos ManesNicolas TentolourisDimitris Voyatzaglou

ITALYGuido MenzingerLuigi UccioliLITHUANIAVytas Dargis Vladimir PetrenkoNETHERLANDSKarel BakkerAUSTRALIAJonathan Shaw

DifferenDifferences ces in cellular infiltrate in cellular infiltrate between acute and chronic between acute and chronic

wounds?wounds?• Cross-sectional study in acute wounds

vs. venous and diabetic ulcers• ECM molecules and cellular infiltrates

compared• Prolonged presence of ECM

molecules noted in dermis of chronic ulcers

• Decreased CD4 T cells, increased B cells and macrophages in chronic ulcers

Loots et al, J. Invest Dermatol, 1998;111:850

““Epidemiology Epidemiology is what you do is what you do when you run out when you run out of ideas”of ideas”

J.D.WardJ.D.Ward

Ethnicity and foot ulceration and amputations

• Diabetic foot ulcers much less common amongst Indian sub-continent Asians in the Manchester area

Toledano et al, 1995

• Amputations 4x more common in Europids compared to Asians in NW UK

Chaturvedi, Abbott et al, Diab Med 2002;19:99

• Ethnicity and Diabetic Neuropathy Ongoing study in NW UK supported by Diabetes UK

Abbott, Chaturvedi et al, 2004

DIABETIC NEUROPATHY

‘PAIN – God’s greatest gift to mankind’

Paul Brand

Future MeetingsFuture Meetings2nd International Meeting on Chronic

Wounds: WUWHS meeting, Paris, France, July 8 – 13th 2004

Cleveland Clinic International Meeting on the Diabetic Foot, 2005

11th Malvern Diabetic Foot Meeting,May 2006

The Diabetic Foot


Charcot Foot

• Common in neuropathic patients• frequently mis-diagnosed• treatable if diagnosed early• suspect in neuropathic patient with

warm, swollen foot• AN UPDATE 2004

• Neuropathy - sensory/autonomic• Increased blood flow• Arteriovenous shunting• Reduced BMD / Osteoporosis• ?Osteoclast activation/bone resorption

Pathogenesis

• Trauma

1. To reduce disease activity

2. To achieve a stable joint

3. To reduce deformity

Treatment Goals

Treatment

• Casting• Non-steroidals• Immobilisation• Radiotherapy• Extra-depth shoes• Pharmacotherapy• Surgery

Pamidronate in Charcot

• Open-labelled trial• 6 patients with acute CNA• Pamidronate 60 mg 2-weekly x6• At each time point:

- Skin temps measured (Mikron infrared thermometer)- Alkaline phosphatase Selby Diabetic Med 1994

0

1

2

3

4T

empe

ratu

re d

iffer

ence

(°C

)

Temperature difference between affected and intact foot

2 4 10 126 8Basal

* * * * *

Weeks of therapySelby Diabetic Med 1994

-30-25

-20-15-10

-5

05

Basal 2 4 6 8 10 12

Weeks of therapy

%ag

e ch

ange

in A

PPercentage change in plasma alkaline

phosphatase

Selby Diabetic Med 1994

Randomised double-blind trial of Pamidronate in

Diabetic Charcot Arthropathy

Jude et al Diabetologia 2001;44:2032

Exeter

London

NottinghamManchester

-3

-2

-1

0

1

0 2 4 6 8 10 12 24 36 52

Weeks

Tem

pera

ture

diff

eren

ce (°

C)

Active

Placebo

Effect of Pamidronate on disease activity

0

5

10

15

20

25

2 4 6 8 10 12 24 36 52

Weeks

BSA

P (u

/l)Effect of Pamidronate on Bone Specific

Alkaline Phosphatase

Active

Placebo* * * * *

0

2

4

6

8

0 2 4 6 8 10 12 24 36 52

Weeks

DPD

(nM

/mM

)

* *

Active

Placebo

Effect of Pamidronate on DPD crosslinks

Discussion

• Bone turnover markers are increased in Charcot arthropathy

• Immobilisation is effective in reducing Charcot activity

• Pamidronate is effective in reducing both disease activity and bone turnover markers

Peak pressure 2nd MTH

0

2

4

6

8

10

12

14

0 500 1000 1500 2000

Peak plantar pressure (kPa)

Plan

tar

tissu

e th

ickn

ess (

mm

) r = - 0.53 (p<0.001)

Conclusions• Plantar tissue thickness measurement is a useful

alternative method to study patients at risk of foot ulceration

• Follow up of these patients will point to the importance of these measurements in clinical practice

Abouaesha et al, Diabetes Care 2001;24:1270

The ‘Instant Total-Contact Cast’

• TCC ‘gold standard’ but labor-intensive, expensive and time-consuming

• Why not use cast-walker or Scotchcast boot made ‘irremovable’

• Removable device wrapped with cohesive bandage (Coband) or plaster

• The device can then be re-attached weekly after removal of bandage and wound inspection

• Conclusions: an ‘instant’ or ‘poor man’s’ TCC Armstrong et al, JAPMA, 2001

Why are trials of removable devices so disappointing?

• When given specialist footwear, only 20% of patients report wearing regularly

• DH walker offloads as well as TCC• DH walker worn for only 28% of daily activity• Conclusions: Despite all good intentions,

offloading devices are used for a minority of daily walking activity

Knowles & Boulton 1996, Lavery et al, 1996 Armstrong et al, 2003

INTERNATIONAL MEETINGS ON THE DIABETIC FOOT

DECEMBER 1988, Howard Johnson 57 Hotel, Boston, Mass, USA

Meeting on Diabetic Foot organized by Bob Frykberg.

In Attendance: Karel Bakker, John Dooren, Jan Rauwerda, Andrew Boulton

‘I don’t like peripheral neuritis – it interferes with work

RD Lawrence, 1923

Neuropathy and Foot Ulceration: Prospective Study

– 169 patients, 22 controls: Manchester, UK– Spectrum of neuropathic deficits. Six year follow

up– 37% ulcers, 11% amputation, 18% died– MNCV best predictor of ulcers, arterial calcification

& PPT, amputation; MNCV,Creatinine & TcPO2 predicted mortality

CONCLUSION: MNCV is the best surrogate endpoint for end-stage neuropathy

Carrington et al, Diabetes Care 2002;25:2010-2015

1362557110 diabetic foot an overview

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